CN103965219A - Vincristine and method for synthesizing vincristine sulfate - Google Patents
Vincristine and method for synthesizing vincristine sulfate Download PDFInfo
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- CN103965219A CN103965219A CN201410203281.0A CN201410203281A CN103965219A CN 103965219 A CN103965219 A CN 103965219A CN 201410203281 A CN201410203281 A CN 201410203281A CN 103965219 A CN103965219 A CN 103965219A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
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Abstract
The invention discloses vincristine and a method for synthesizing vincristine sulfate. The method for synthesizing vincristine comprises the following steps: 1) preparing vinblastine; and 2) synthesizing, purifying and refining vincristine, namely carrying out reaction on the synthesized vincristine and ethanol sulfate on the basis of the method for synthesizing vincristine, so as to obtain a crude product of the vincristine sulfate, and refining the crude product of the vincristine sulfate to obtain the vincristine sulfate. The vincristine is synthesized by adopting a one-step synthesis method when the vincristine is synthesized, the synthetic route of the vincristine is simplified, the method is simple in synthetic route, and low in production cost, the purity of the synthesized vincristine can be up to over 96% after the synthesized vincristine is refined, and the vincristine sulfate is synthesized on the basis of the method for synthesizing the vincristine. The process for synthesizing the vincristine is simple, so that the synthetic route of the vincristine sulfate is greatly simplified, the method is simple in synthetic route, and low in production cost, and the purity of the refined vincristine sulfate can be up to over 96%.
Description
Technical field
The present invention relates to the synthetic method of vincristine(VCR) and vincristine sulphate, belong to the technical field of alkaloid formulations.
Technical background
Vincristine(VCR) is Benzazole compounds, its chemical structure be one contain indole nucleus condense tetra-atomic ring and another five-ring that condenses that contains indoline core is directly formed by connecting with carbon-carbon bond, have 9 asymmetric centers.Vincristine(VCR) has the effect that cell fission of making (mitotic division) stopped in mid-term, equally with colchicine can suppress with tubulin binding its biological activity, but combining site difference, and effect is stronger than colchicine.What vincristine(VCR) was different from colchicine is also works as Actin muscle and 10 nano-filaments albumen etc. to the protein beyond tubulin, particularly more effective to the tumour of hemocytopoietic organ, vincristine(VCR) is employed as one of carcinostatic agent on clinical medicine.Vincristine(VCR) can be anticancer, and curative effect is approximately higher 10 times than vinealeucoblastine(VLB).Can be used for treating acute lymphoblastic leukemia, curative effect is better, also effective in cure to other acute leukemias, Hokdkin disease, lymphosarcoma, reticulum cell sarcoma and mammary cancer.Vincristine sulphate can be anticancer, is mainly used in treating acute lymphoblastic leukemia, Hokdkin disease, malignant lymphoma, small cell lung cancer, mammary cancer, ovarian cancer, digestive tract cancer etc.At present, the raw material of synthetic vincristine sulphate is mainly vincristine(VCR) both at home and abroad, and therefore, a step of the most critical of synthetic vincristine sulphate is synthetic vincristine(VCR) still.
At present, the technology of the synthetic vincristine(VCR) of research is also a lot of both at home and abroad, although can obtain vincristine(VCR), all has various problems.
Chinese invention patent " a kind of method of producing vinealeucoblastine(VLB) and/or vincristine(VCR) " (application number: 200810117768.1) disclose a kind of method of producing vinealeucoblastine(VLB) and/or vincristine(VCR), the method is that the strain of Vinca polyploid cell is inoculated in synthetic medium, in 20～29 DEG C, cultivate the cell that obtains being rich in vinealeucoblastine(VLB) and vincristine(VCR) for 3～7 days.The method is used cell and substratum technology, and cost is high, complex process, and the production cycle is long, is unfavorable for scale operation.
Synthetic vincristine(VCR) is modal synthetic taking vincaleucoblastine vitriol as raw material.Concrete grammar with the synthetic vincristine(VCR) of vincaleucoblastine vitriol is as follows: the first step, first vincaleucoblastine vitriol is dissolved in water, the pH value of regulator solution is to acid, be placed in ice bath (70 DEG C), add chromic acid and carry out oxidizing reaction, react after 15 minutes, adding strong aqua alkalizes again, with dichloromethane extraction, reclaim solvent to dry, obtain enriched material; Second step; the enriched material thing that the first step is obtained adds in formic acid; carry out formylation, then use dichloromethane extraction, reclaim organic solvent to dry; go up again alumina column and carry out chromatography; collect containing vincristine(VCR) stream part, merge same stream part, reclaim organic solvent to dry; further salify and refining, is drying to obtain vincristine(VCR).The method adopts two step synthesis methods to synthesize vincristine(VCR), processing step complexity, and production cost is high.
Summary of the invention
The problem existing for overcoming prior art, the invention provides the synthetic method of vincristine(VCR) and vincristine sulphate, in the time of synthetic vincristine(VCR), adopt the synthetic vincristine(VCR) of one-step synthesis, simplify the synthetic route of vincristine(VCR), operational path is simple, and production cost is low, synthetic vincristine(VCR) after refining purity up to more than 96%.Synthetic vincristine sulphate on synthetic vincristine(VCR) method basis, because the technique of synthetic vincristine(VCR) is simple, thereby has significantly simplified the synthetic route of vincristine sulphate, and operational path is simple, and production cost is low, and purity reaches more than 96% after refining.
Realizing the technical scheme that the object of the invention takes is:
A synthetic method for vincristine(VCR), comprises the steps:
1) preparation of vincaleucoblastine
Vincaleucoblastine vitriol is added to the water, being mixed with concentration is the vincaleucoblastine sulfate liquor of 0.2～0.26g/mL, then add ammoniacal liquor to regulate pH value to 7.5～8 of vincaleucoblastine sulfate liquor, add again enough methylene dichloride to extract, after layering, remove supernatant liquid, lower floor's organic phase is spin-dried for, in vacuum, drain, obtain vincaleucoblastine;
2) vincristine(VCR) is synthetic
Vincaleucoblastine is dissolved in tetrahydrofuran (THF), being mixed with concentration is the vincaleucoblastine tetrahydrofuran solution of 0.02～0.025g/mL, then the reaction vessel that fills vincaleucoblastine tetrahydrofuran solution is placed in to cryogenic thermostat reactive bath technique, acetic acid is added in vincaleucoblastine tetrahydrofuran solution, wherein the mass volume ratio of vincaleucoblastine and acetic acid is vincaleucoblastine: acetic acid=0.25～0.3g/mL, , in the time that the temperature of cryogenic thermostat reactive bath technique is down to-63～-67 DEG C, insulation, under constant temperature, drip the sodium dichromate solution of concentration as 0.15～0.2g/mL taking the speed of 10～15mL/min, wherein the mass ratio of vincaleucoblastine and sodium dichromate 99 is vincaleucoblastine: sodium dichromate 99=1:1.60, in reaction gains, drip ammoniacal liquor after completion of the reaction, regulate pH value to 3.5～4, generate throw out, reaction vessel is shifted out after cryogenic thermostat reactive bath technique, in reaction vessel, add purified water dissolution precipitation thing, add again ammoniacal liquor to regulate pH value to 8～9, generate again throw out, add trichloromethane dissolution precipitation thing, filter to get filtrate, by filtrate stratification, remove supernatant liquid, lower floor's organic phase is spin-dried for, drain in a vacuum, obtain dark-brown vincristine(VCR) crude product.
Vincristine(VCR) crude product is carried out to purifying, obtain vincristine(VCR) purifying product, the purifying of vincristine(VCR) crude product comprises the steps:
1. trichloromethane: anhydrous methanol=99.5:0.5 by volume, trichloromethane is mixed with anhydrous methanol and is mixed with eluent 1, first in chromatography column, add part eluent 1 rinse chromatography column, take again 200～300 object column layer chromatography silicone rubbers, column layer chromatography silicone rubber is joined in remaining eluent 1, after stirring, pack in chromatography column cut-out tap after chromatography column is walked completely into;
2. trichloromethane: anhydrous methanol=99:1 by volume, trichloromethane is mixed to preparation eluent 2 with anhydrous methanol, press mass volume ratio vincristine(VCR) crude product: trichloromethane=0.56g/mL～0.7g/mL, vincristine(VCR) crude product is added in trichloromethane, after dissolving completely, add in chromatography column, eluent 2 is carried out to wash-out with the flow velocity of 45～55mL/min to chromatography column, until sample colour band is down to chromatography column bottom, till color appears in receiving bottle;
3. change sample colour band, trichloromethane by volume: anhydrous methanol=98.5:1.5, mixes trichloromethane and is mixed with eluent 3 with anhydrous methanol, eluent 3 is carried out to wash-out with the flow velocity of 45～55mL/min to chromatography column, until sample colour band is down to pillar bottom, change receiving bottle, eluent 4 taking volume as chromatography column volume repeats chromatography column to carry out wash-out with the flow velocity of 45～55mL/min again, taking eluent 3 as benchmark, when each repetition elution chromatography post, in eluent 4, the content of anhydrous methane increases progressively 0.5% when the more last wash-out of volumn concentration of anhydrous methanol, when the more last wash-out of volumn concentration of trichloromethane, the content of trichloromethane successively decreases 0.5%, start to receive the liquid of chromatographic column effluent simultaneously, the liquid of chromatographic column effluent is receiving liquid, and detect the purity of vincristine(VCR) in receiving liquid, in the time of purity >=60% of vincristine(VCR) in receiving liquid, start to collect receiving liquid, in the time of the purity <60% of vincristine(VCR) in receiving liquid, stop collecting receiving liquid,
4. the receiving liquid of collection is carried out to concentrated by rotary evaporation, revolving and steaming temperature is 26～30 DEG C, pressure is-0.1MPa～-0.08MPa, revolve and steam to till not having reflux solvent to drip in return line 3 seconds, the enriched material now revolving after steaming is sticky silk fabric shape, stop revolving steaming, then enriched material vacuum is drained, obtain vincristine(VCR) purifying product.
The method that above-mentioned steps detects the purity of vincristine(VCR) in receiving liquid in is 3. as follows:
Sherwood oil by volume: trichloromethane: acetone: diethylamine=6:3:0.5:0.6, by sherwood oil, trichloromethane, acetone and diethylamine mix as developping agent, the vincristine(VCR) of purity >=70% is dissolved in to the vincristine(VCR) chloroform soln that obtains after trichloromethane in contrast, receiving liquid and vincristine(VCR) chloroform soln are analyzed with thin layer chromatography, colour band distribution situation after separating in thin layer chromatography board with vincristine(VCR) chloroform soln by ultraviolet analysis instrument for three purposed observation receiving liquid, colour band after both separate in thin layer chromatography board distributes when identical, this receiving liquid is detected to the purity of vincristine(VCR) in this receiving liquid by high performance liquid chromatography, in the time of purity >=60% of vincristine(VCR) in this receiving liquid, collect immediately receiving liquid, when colour band after observing both with ultraviolet analysis instrument for three purposed and separating in thin layer chromatography board is distributed with difference, now vincristine(VCR) sample spot desalination, impure point is denseer, again this receiving liquid is detected to the purity of vincristine(VCR) in this receiving liquid by high performance liquid chromatography, in the time of the purity <60% of vincristine(VCR) in this receiving liquid (purity is less than 60% receiving liquid and how processes), stop collecting receiving liquid,
Vincristine(VCR) purifying product are refined, obtained vincristine(VCR), refining the comprising the steps: of vincristine(VCR) purifying product
Press mass volume ratio vincristine(VCR) purifying product: anhydrous methanol=1:2, vincristine(VCR) purifying product are added in dehydrated alcohol, under 38～42 DEG C of water bath condition, dissolve, after dissolving completely, use ultrasonic echography, after having Precipitation, at-20～-30 DEG C, refrigerate, until Precipitation is complete, use solvent filter suction filtration, filter cake is washed with anhydrous methanol, again the filter cake after washing is dissolved with enough methylene dichloride, after dissolving, be spin-dried for, vacuum is drained, to drain gains and carry out recrystallization with anhydrous methanol at-20～-30 DEG C, at least recrystallization 5 times, obtain white vincristine(VCR).
To drain gains and carry out recrystallization 5 times with anhydrous methanol under-20～-30 DEG C of conditions, the volume of the anhydrous methanol adding when each recrystallization is followed successively by drains 2.2,2.4,2.8,2.6 and 3 times of gains quality.
The present invention also provides a kind of method based on the synthetic synthetic vincristine sulphate of method of vincristine(VCR), comprises the steps:
1) preparation of vincaleucoblastine
Vincaleucoblastine vitriol is added to the water, being mixed with concentration is the vincaleucoblastine sulfate liquor of 0.2～0.26g/mL, then add ammoniacal liquor to regulate pH value to 7.5～8 of vincaleucoblastine sulfate liquor, add again enough methylene dichloride to extract, after layering, remove supernatant liquid, lower floor's organic phase is spin-dried for, in vacuum, drain, obtain vincaleucoblastine;
2) vincristine(VCR) is synthetic
Vincaleucoblastine is dissolved in tetrahydrofuran (THF), being mixed with concentration is the vincaleucoblastine tetrahydrofuran solution of 0.02～0.025g/mL, then the reaction vessel that fills vincaleucoblastine tetrahydrofuran solution is placed in to cryogenic thermostat reactive bath technique, acetic acid is added in vincaleucoblastine tetrahydrofuran solution, wherein the mass volume ratio of vincaleucoblastine and acetic acid is vincaleucoblastine: acetic acid=0.25～0.3g/mL, , in the time that the temperature of cryogenic thermostat reactive bath technique is down to-63～-67 DEG C, insulation, under constant temperature, drip the sodium dichromate solution of concentration as 0.15～0.2g/mL taking the speed of 10～15mL/min, wherein the mass ratio of vincaleucoblastine and sodium dichromate 99 is vincaleucoblastine: sodium dichromate 99=1:1.60, in reaction gains, drip ammoniacal liquor after completion of the reaction, regulate pH value to 3.5～4, generate throw out, reaction vessel is shifted out after cryogenic thermostat reactive bath technique, in reaction vessel, add purified water dissolution precipitation thing, add again ammoniacal liquor to regulate pH value to 8～9, generate again throw out, add trichloromethane dissolution precipitation thing, filter to get filtrate, by filtrate stratification, remove supernatant liquid, lower floor's organic phase is spin-dried for, drain in a vacuum, obtain dark-brown vincristine(VCR) crude product.
3) vincristine sulphate is synthetic
By vincristine(VCR) crude product carry out purifying and refining after the vincristine(VCR) of gained be dissolved in and in ethanol, obtain vincristine(VCR) ethanolic soln, wherein the mass volume ratio of vincristine(VCR) and ethanol is vincristine(VCR): ethanol=1:3g/mL, under agitation condition, drip the ethanol solution of sulfuric acid of concentration of volume percent as 5% in taking the speed of 20～30mL/min to vincristine(VCR) ethanolic soln, produce white precipitate, in the time that the pH of solution value is 3.8～4.1, adding quality is the ethanol that boils of 30 times of vincristine(VCR) quality, at-20～-30 DEG C, refrigeration is complete to precipitation again, suction filtration, by filter cake ice washing with alcohol, after vacuum is drained, carry out normal temperature drying under reduced pressure and must be dried thing, to be dried thing further refining, obtain white vincristine sulphate.
Step 3) in dry the refining of thing comprise the steps:
Dry thing is dissolved by enough purified water, be then placed in freeze drier cold-trap, at-53～-57 DEG C, after precooling, drying under reduced pressure, obtains white vincristine sulphate.
In vincristine(VCR) synthetic method provided by the invention, first vincaleucoblastine vitriol is dissociated and obtains vincaleucoblastine, this step is a kind of simple neutralizing treatment, and then vincaleucoblastine is carried out to redox reaction under the condition of acetic acid and potassium bichromate existence, directly obtain vincristine(VCR), vincaleucoblastine is carried out oxidation step reduction reaction by this step, obtains vincristine(VCR).The present invention also provides the synthetic method of vincristine sulphate, and the method is synthetic vincristine sulphate on the basis of synthetic vincristine(VCR), and synthetic vincristine(VCR) is reacted with sulfuric acid ethanol, obtains vincristine sulphate.
Compared with prior art, its beneficial effect and advantage are in the present invention:
1) the method adopts one-step synthesis can obtain vincristine(VCR), and operational path is simple, has greatly saved production cost, is applicable to scale operation; The synthetic vincristine sulphate taking the synthetic vincristine(VCR) of the present invention as raw material, because the technique of synthetic vincristine(VCR) is simple, cost is low, therefore will significantly reduce the cost of synthetic vincristine sulphate, simplifies the technical process of synthetic vincristine sulphate.
2) the method adopts the synthetic vincristine(VCR) of one-step method for synthesizing, greatly shorten the time of synthetic vincristine(VCR), synthetic vincristine sulphate on the basis of the synthetic vincristine(VCR) of this method, the production cycle of whole vincristine sulphate only needs 12 hours, compared with prior art, significantly reduced the production cycle of vincristine sulphate.
3) reagent that the method is used is common agents, and the instrument of use is General Instrument, and therefore, the production cost of the method is low.
4) synthetic vincristine(VCR) and the vincristine sulphate purity of the method is high, and quality percentage composition >=96% of vincristine(VCR) is single assorted≤1%, total assorted≤4.0%, quality percentage composition >=96% of vincristine sulphate, single assorted≤1%, total assorted≤4.0%.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1
Take vincaleucoblastine vitriol 100g, add in 500mL purified water, after dissolving completely, add the pH value to 7.5 of 16.5mL ammoniacal liquor regulator solution, then add enough methylene dichloride to extract, after layering, remove supernatant liquid, lower floor's organic phase is concentrated, is spin-dried for Rotary Evaporators, then drain with vacuum oil pump, obtain 85g pale yellow powder vincaleucoblastine.
Take 50g vincaleucoblastine, add in 2500mL tetrahydrofuran (THF), being mixed with concentration is the vincaleucoblastine solution of 0.02g/mL, then vincaleucoblastine tetrahydrofuran solution is placed in to cryogenic thermostat reactive bath technique, in vincaleucoblastine solution, drip 187.5mL acetic acid, in the time that the temperature of cryogenic thermostat reactive bath technique is down to-65 DEG C, insulation, drip the sodium dichromate solution of 445mL concentration as 0.18g/mL taking the speed of 12mL/min, dropwise rear continuation reaction 2 hours, in reaction gains, drip ammoniacal liquor, regulate pH value to 3.8, generate throw out, shift out cryogenic thermostat reactive bath technique, add 1000mL purified water dissolution precipitation thing, add again ammoniacal liquor to regulate pH value to 8, generate again throw out, add 1000mL trichloromethane dissolution precipitation thing, filter to get filtrate, by filtrate stratification, concentrated with Rotary Evaporators, be spin-dried for, drain with vacuum oil pump, obtain vincristine(VCR) crude product 57.5g.
Trichloromethane by volume: anhydrous methanol=99.5:0.5, mixes trichloromethane and is mixed with eluent 1 with anhydrous methanol, prepare altogether 4L.Getting specification is
the chromatography column of inch × 1000mm, first in chromatography column post, add 1L eluent 1 rinse chromatography column, take 2kg200 object column layer chromatography silicone rubber, in column layer chromatography silicone rubber, add 3L eluent 1, after stirring, pack in chromatography column cut-out tap after chromatography column is walked completely into.
Trichloromethane by volume: anhydrous methanol=99:1, trichloromethane is mixed with anhydrous methanol and is mixed with eluent 2, take vincristine(VCR) crude product 140g, vincristine(VCR) crude product is added in 230mL trichloromethane, after dissolving completely, add in chromatography column, eluent 2 is carried out to wash-out with the flow velocity of 50mL/min to chromatography column, until sample colour band is down to chromatography column bottom, till color appears in receiving bottle.
Change sample colour band, trichloromethane by volume: anhydrous methanol=98.5:1.5, trichloromethane and anhydrous methanol are mixed to preparation eluent 3, prepare altogether 4L, eluent 3 is carried out to wash-out with the flow velocity of 50mL/min to chromatography column, until sample colour band is down to pillar bottom, change receiving bottle, eluent 4 taking volume as 12L repeats chromatography column to carry out wash-out with the flow velocity of 45mL/min again, taking eluent 3 as benchmark, when each repetition elution chromatography post, in eluent 4, the content of anhydrous methanol increases progressively 0.5% when the more last wash-out of volumn concentration of anhydrous methanol, when the more last wash-out of volumn concentration of trichloromethane, the content of trichloromethane successively decreases 0.5%, start to receive the liquid of chromatographic column effluent simultaneously, the liquid of chromatographic column effluent is receiving liquid, sherwood oil by volume: trichloromethane: acetone: diethylamine=6:3:0.5:0.6, by sherwood oil, trichloromethane, acetone and diethylamine mix as developping agent, the vincristine(VCR) of purity >=70% is dissolved in to the vincristine(VCR) chloroform soln that obtains after trichloromethane in contrast, receiving liquid and vincristine(VCR) chloroform soln are analyzed with thin layer chromatography, colour band distribution situation after separating in thin layer chromatography board with vincristine(VCR) chloroform soln by ultraviolet analysis instrument for three purposed observation receiving liquid, colour band after both separate in thin layer chromatography board distributes when identical, receiving liquid is now detected to the purity of vincristine(VCR) in this receiving liquid by high performance liquid chromatography, in the time of purity >=60% of vincristine(VCR) in this receiving liquid, collect immediately receiving liquid, when colour band after observing both with ultraviolet analysis instrument for three purposed and separating in thin layer chromatography board is distributed with difference, now vincristine(VCR) sample spot desalination, impure point is denseer, again receiving liquid is now detected to the purity of vincristine(VCR) in this receiving liquid by high performance liquid chromatography, in the time of the purity <60% of vincristine(VCR) in this receiving liquid, stop collecting receiving liquid,
The receiving liquid of collection is transferred in 1L single port flask with triangular funnel, start to revolve steaming, revolving and steaming temperature is 29 DEG C, pressure is-0.09MPa, revolve and steam to till not having reflux solvent to drip in return line 3 seconds, the enriched material now revolving after steaming is sticky silk fabric shape, stops revolving steaming, then enriched material is taken out 2 hours with rotary-vane vaccum pump, obtained vincristine(VCR) purifying product.
Take vincristine(VCR) purifying product 180g, join in 360mL anhydrous methanol, and dissolve in 40 DEG C of water-baths, after dissolving completely, with ultrasonic echography, at-24 DEG C, refrigerate 2 hours after having Precipitation, until there are a large amount of white precipitates to separate out in a large number.With 1L solvent filter suction filtration, by 50mL anhydrous methanol washing for filter cake, again the filter cake after washing is dissolved with 500mL methylene dichloride, after dissolving, be spin-dried for Rotary Evaporators, drain 2 hours with vacuum oil pump again, will drain gains and carry out recrystallization with anhydrous methanol at-24 DEG C, recrystallization 5 times, the volume of the anhydrous methanol adding when each recrystallization is followed successively by drains 2.2,2.4,2.8,2.6 and 3 times of gains quality, obtains white vincristine(VCR).After testing, the quality percentage composition of gained vincristine(VCR) is 97.8%, and singly mixing is 0.7%, and always mixing is 2.2%.
Take vincristine(VCR) purifying product 103g, after being dissolved in 309mL dehydrated alcohol, stir, first drip the sulfuric acid ethanol of concentration of volume percent as 5% taking the speed of 20mL/min, separate out until there is a large amount of white precipitates, in the time that the pH of solution value is 3.8, adding quality is 30 times of ethanol that boil of vincristine(VCR) quality, deepfreeze 2 hours under-25 DEG C of conditions again, suction filtration, by filter cake ice washing with alcohol, vacuum is drained, be transferred in vacuum drying oven normal temperature drying under reduced pressure 3 hours, obtain dry thing, dry thing is dissolved by the purified water that volume is 6 times of dry substance amounts, then be placed in freeze drier cold-trap, under-56 DEG C of conditions, precooling is after 5 hours, drying under reduced pressure 24 hours, obtain white vincristine sulphate.After testing, the quality percentage composition of vincristine sulphate is 97.7%, and singly mixing is 0.68%, and always mixing is 2.3%.
Embodiment 2
Take vincaleucoblastine vitriol 100g, add in 380mL purified water, after dissolving completely, add the pH value to 8 of 18mL ammoniacal liquor regulator solution, then add enough methylene dichloride to extract, after layering, remove supernatant liquid, lower floor's organic phase is concentrated, is spin-dried for Rotary Evaporators, then drain with vacuum oil pump, obtain 81g pale yellow powder vincaleucoblastine.
Take 50g vincaleucoblastine, add in 2000mL tetrahydrofuran (THF), being mixed with concentration is the vincaleucoblastine solution of 0.025g/mL, then vincaleucoblastine tetrahydrofuran solution is placed in to cryogenic thermostat reactive bath technique, in vincaleucoblastine solution, drip 187.5mL acetic acid, in the time that the temperature of cryogenic thermostat reactive bath technique is down to-63 DEG C, insulation, drip the sodium dichromate solution of 445mL concentration as 0.18g/mL taking the speed of 14mL/min, dropwise rear continuation reaction 2.2 hours, in reaction gains, drip ammoniacal liquor, regulate pH value to 3.6, generate throw out, shift out cryogenic thermostat reactive bath technique, add 900mL purified water dissolution precipitation thing, add again ammoniacal liquor to regulate pH value to 8.5, generate again throw out, add 900mL trichloromethane dissolution precipitation thing, filter to get filtrate, by filtrate stratification, concentrated with Rotary Evaporators, be spin-dried for, drain with vacuum oil pump, obtain vincristine(VCR) crude product 54.2g.
Trichloromethane by volume: anhydrous methanol=99.5:0.5, mixes trichloromethane and is mixed with eluent 1 with anhydrous methanol, prepare altogether 4.2L.Getting specification is
inch × 1000mm chromatography column adds 1.2L eluent 1 in chromatography column post, takes 1.9kg300 object column layer chromatography silicone rubber, in column layer chromatography silicone rubber, adds 3.2L eluent 1, packs in chromatography column cut-out tap after chromatography column is walked completely after stirring into.
Trichloromethane by volume: anhydrous methanol=99:1, mixes trichloromethane and is mixed with eluent 2 with anhydrous methanol.Take vincristine(VCR) crude product 135g, vincristine(VCR) crude product is added in 220mL trichloromethane, after dissolving completely, add in chromatography column, eluent 2 is carried out to wash-out with the flow velocity of 52mL/min to chromatography column, until sample colour band is down to chromatography column bottom, till color appears in receiving bottle.
Change sample colour band, trichloromethane by volume: anhydrous methanol=98.5:1.5, trichloromethane and anhydrous methanol are mixed to preparation eluent 3, prepare altogether 4L, eluent 3 is carried out to wash-out with the flow velocity of 52mL/min to chromatography column, until sample colour band is down to pillar bottom, change receiving bottle, eluent 4 taking volume as 12L repeats chromatography column to carry out wash-out with the flow velocity of 55mL/min again, taking eluent 3 as benchmark, when each repetition elution chromatography post, in eluent 4, the content of anhydrous methanol increases progressively 0.5% when the more last wash-out of volumn concentration of anhydrous methanol, when the more last wash-out of volumn concentration of trichloromethane, the content of trichloromethane successively decreases 0.5%, start to receive the liquid of chromatographic column effluent simultaneously, the liquid of chromatographic column effluent is receiving liquid, sherwood oil by volume: trichloromethane: acetone: diethylamine=6:3:0.5:0.6, by sherwood oil, trichloromethane, acetone and diethylamine mix as developping agent, the vincristine(VCR) of purity >=70% is dissolved in to the vincristine(VCR) chloroform soln that obtains after trichloromethane in contrast, receiving liquid and vincristine(VCR) chloroform soln are analyzed with thin layer chromatography, colour band distribution situation after separating in thin layer chromatography board with vincristine(VCR) chloroform soln by ultraviolet analysis instrument for three purposed observation receiving liquid, colour band after both separate in thin layer chromatography board distributes when identical, receiving liquid is now detected to the purity of vincristine(VCR) in this receiving liquid by high performance liquid chromatography, in the time of purity >=60% of vincristine(VCR) in this receiving liquid, collect immediately receiving liquid, when colour band after observing both with ultraviolet analysis instrument for three purposed and separating in thin layer chromatography board is distributed with difference, now vincristine(VCR) sample spot desalination, impure point is denseer, again receiving liquid is now detected to the purity of vincristine(VCR) in this receiving liquid by high performance liquid chromatography, in the time of the purity <60% of vincristine(VCR) in this receiving liquid, stop collecting receiving liquid.
The receiving liquid of collection is transferred in 1L single port flask with triangular funnel, start to revolve steaming, revolving and steaming temperature is 29 DEG C, pressure is-0.095MPa, revolving to steam in return line 3 seconds does not have reflux solvent to drip, and the enriched material now revolving after steaming is sticky silk fabric shape, stops revolving steaming, then enriched material vacuum is drained, obtained vincristine(VCR) purifying product.
Take vincristine(VCR) purifying product 175g, join in the anhydrous methanol of 350mL, and dissolve in 41 DEG C of water-baths, after dissolving completely, with ultrasonic echography, at-22 DEG C, refrigerate 2 hours after having Precipitation, until there are a large amount of white precipitates to separate out in a large number.With 1L solvent filter suction filtration, by 50mL anhydrous methanol washing for filter cake, again the filter cake after washing is dissolved with 500mL methylene dichloride, be spin-dried for Rotary Evaporators, vacuum is drained 2.2 hours, will drain gains and carry out recrystallization with anhydrous methanol at-24 DEG C, recrystallization 5 times, the volume of the anhydrous methanol adding when each recrystallization is followed successively by drains 2.2,2.4,2.8,2.6 and 3 times of gains quality, obtains white vincristine(VCR).After testing, the quality percentage composition of gained vincristine(VCR) is 98.0%, and singly mixing is 0.66%, and always mixing is 2.0%.
Take vincristine(VCR) purifying product 105g, after being dissolved in 315mL dehydrated alcohol, stir, first drip the sulfuric acid ethanol of concentration of volume percent as 5% taking the speed of 25mL/min, separate out until there is a large amount of white precipitates, in the time that the pH of solution value is 3.8, adding quality is 30 times of ethanol that boil of vincristine(VCR) quality, at-26 DEG C, refrigerate 2 hours again, suction filtration, by filter cake ice washing with alcohol, vacuum is drained, be transferred in vacuum drying oven normal temperature drying under reduced pressure 2 hours, obtain dry thing, dry thing is dissolved by the purified water that volume is 6 times of dry substance amounts, then be placed in freeze drier cold-trap, under-56 DEG C of conditions, precooling is after 5 hours, drying under reduced pressure 23 hours, obtain white vincristine sulphate.After testing, the quality percentage composition of vincristine sulphate is 98.5%, and singly mixing is 0.6%, and always mixing is 2.4%.
Embodiment 3
Take vincaleucoblastine vitriol 100g, add in 450mL purified water, after dissolving completely, add the pH value to 8.0 of 16mL ammoniacal liquor regulator solution, then add enough methylene dichloride to extract, after layering, remove supernatant liquid, lower floor's organic phase is concentrated, is spin-dried for Rotary Evaporators, then drain with vacuum oil pump, obtain 82.6g pale yellow powder vincaleucoblastine.
Take 50g vincaleucoblastine, add in 2250mL tetrahydrofuran (THF), being mixed with concentration is the vincaleucoblastine solution of 0.022g/mL, then vincaleucoblastine tetrahydrofuran solution is placed in to cryogenic thermostat reactive bath technique, in vincaleucoblastine solution, drip 187.5mL acetic acid, in the time that the temperature of cryogenic thermostat reactive bath technique is down to-67 DEG C, insulation, drip the sodium dichromate solution of 445mL concentration as 0.18g/mL taking the speed of 12mL/min, dropwise rear continuation reaction 2.3 hours, in reaction gains, drip ammoniacal liquor, regulate pH value to 3.5, generate throw out, shift out cryogenic thermostat reactive bath technique, add 850mL purified water dissolution precipitation thing, add again ammoniacal liquor to regulate pH value to 8.6, generate again throw out, add 800mL trichloromethane dissolution precipitation thing, filter to get filtrate, by filtrate stratification, concentrated with Rotary Evaporators, be spin-dried for, drain with vacuum oil pump, obtain vincristine(VCR) crude product 52.5g.
By volume ratio trichloromethane: anhydrous methanol=99.5:0.5, trichloromethane is mixed to preparation eluent 1 with dehydrated alcohol, prepare altogether 4L, get specification and be
the chromatography column of inch × 1000mm adds 1L eluent 1 in chromatography column post, takes 2kg200 object column layer chromatography silicone rubber, in column layer chromatography silicone rubber, adds 3L eluent 1, packs in chromatography column cut-out tap after chromatography column is walked completely after stirring into.
Trichloromethane by volume: dehydrated alcohol=99:1, trichloromethane is mixed with anhydrous methanol and is mixed with eluent 2, take vincristine(VCR) crude product 138g, vincristine(VCR) crude product is added in 240mL trichloromethane, after dissolving completely, add in chromatography column, eluent 2 is carried out to wash-out with the flow velocity of 49mL/min to chromatography column, until sample colour band is down to chromatography column bottom, till color appears in receiving bottle.
Change sample colour band, trichloromethane by volume: anhydrous methanol=98.5:1.5, trichloromethane and anhydrous methanol are mixed to preparation eluent 3, prepare altogether 4L, eluent 3 is carried out to wash-out with the flow velocity of 50mL/min to chromatography column with the flow velocity of 49mL/min, until sample colour band is down to pillar bottom, change receiving bottle, eluent 4 taking volume as 12L repeats chromatography column to carry out wash-out again, taking eluent 3 as benchmark, when each repetition elution chromatography post, in eluent 4, the content of anhydrous methanol increases progressively 0.5% when the more last wash-out of volumn concentration of anhydrous methanol, when the more last wash-out of volumn concentration of trichloromethane, the content of trichloromethane successively decreases 0.5%, start to receive the liquid of chromatographic column effluent simultaneously, the liquid of chromatographic column effluent is receiving liquid, sherwood oil by volume: trichloromethane: acetone: diethylamine=6:3:0.5:0.6, by sherwood oil, trichloromethane, acetone and diethylamine mix as developping agent, the vincristine(VCR) of purity >=70% is dissolved in to the vincristine(VCR) chloroform soln that obtains after trichloromethane in contrast, receiving liquid and vincristine(VCR) chloroform soln are analyzed with thin layer chromatography, colour band distribution situation after separating in thin layer chromatography board with vincristine(VCR) chloroform soln by ultraviolet analysis instrument for three purposed observation receiving liquid, colour band after both separate in thin layer chromatography board distributes when identical, receiving liquid is now detected to the purity of vincristine(VCR) in this receiving liquid by high performance liquid chromatography, in the time of purity >=60% of vincristine(VCR) in this receiving liquid, collect immediately receiving liquid, when colour band after observing both with ultraviolet analysis instrument for three purposed and separating in thin layer chromatography board is distributed with difference, now vincristine(VCR) sample spot desalination, impure point is denseer, again receiving liquid is now detected to the purity of vincristine(VCR) in this receiving liquid by high performance liquid chromatography, in the time of the purity <60% of vincristine(VCR) in this receiving liquid, stop collecting receiving liquid.
The receiving liquid of collection is transferred in 1L single port flask with triangular funnel, start to revolve steaming, revolving and steaming temperature is 28.5 DEG C, pressure is-0.085MPa, revolving to steam in return line 3 seconds does not have reflux solvent to drip, and the enriched material now revolving after steaming is sticky silk fabric shape, stops revolving steaming, then enriched material vacuum is drained, obtained vincristine(VCR) purifying product.
Take vincristine(VCR) purifying product 138g, in the 276mL anhydrous methanol adding, and dissolve in 41 DEG C of water-baths, after dissolving completely, with ultrasonic echography, at-25 DEG C, refrigerate 2 hours after having Precipitation, until there are a large amount of white precipitates to separate out in a large number.With 1L solvent filter suction filtration, by 50mL anhydrous methanol washing for filter cake, again the filter cake after washing is dissolved with 500mL methylene dichloride, be spin-dried for Rotary Evaporators, drain 2 hours with vacuum oil pump, will drain gains and carry out recrystallization with anhydrous methanol at-25 DEG C, recrystallization 5 times, the volume of the anhydrous methanol adding when each recrystallization is followed successively by drains 2.2,2.4,2.8,2.6 and 3 times of gains quality, obtains white vincristine(VCR).The quality percentage composition of gained vincristine(VCR) is 98.4%, and singly mixing is 0.58%, and always mixing is 1.6%.
Take vincristine(VCR) purifying product 105g, after being dissolved in 315mL ethanol, stir, first drip the sulfuric acid ethanol of concentration of volume percent as 5% taking the speed of 30mL/min, separate out until there is a large amount of white precipitates, in the time that the pH of solution value is 3.9, adding quality is 30 times of ethanol that boil of vincristine(VCR) quality, deepfreeze 2 hours under-25 DEG C of conditions again, suction filtration, by filter cake ice washing with alcohol, after vacuum is drained, be transferred in vacuum drying oven normal temperature drying under reduced pressure 2 hours, obtain dry thing, dry thing is dissolved by the purified water that volume is 6 times of dry substance amounts, then be placed in freeze drier cold-trap, at-54 DEG C, precooling is after 5 hours, drying under reduced pressure 23 hours, obtain white vincristine sulphate.After testing, the quality percentage composition of vincristine sulphate is 98.5%, and singly mixing is 0.56%, and always mixing is 1.5%.
Claims (7)
1. a synthetic method for vincristine(VCR), is characterized in that comprising the steps:
1) preparation of vincaleucoblastine
Vincaleucoblastine vitriol is added to the water, being mixed with concentration is the vincaleucoblastine sulfate liquor of 0.2～0.26g/mL, then add ammoniacal liquor to regulate pH value to 7.5～8 of vincaleucoblastine sulfate liquor, add again enough methylene dichloride to extract, after layering, remove supernatant liquid, lower floor's organic phase is spin-dried for, in vacuum, drain, obtain vincaleucoblastine;
2) vincristine(VCR) is synthetic
Vincaleucoblastine is dissolved in tetrahydrofuran (THF), being mixed with concentration is the vincaleucoblastine tetrahydrofuran solution of 0.02～0.025g/mL, then the reaction vessel that fills vincaleucoblastine tetrahydrofuran solution is placed in to cryogenic thermostat reactive bath technique, acetic acid is added in vincaleucoblastine tetrahydrofuran solution, wherein the mass volume ratio of vincaleucoblastine and acetic acid is vincaleucoblastine: acetic acid=0.25～0.3g/mL, , in the time that the temperature of cryogenic thermostat reactive bath technique is down to-63～-67 DEG C, insulation, under constant temperature, drip the sodium dichromate solution of concentration as 0.15～0.2g/mL taking the speed of 10～15mL/min, wherein the mass ratio of vincaleucoblastine and sodium dichromate 99 is vincaleucoblastine: sodium dichromate 99=1:1.60, in reaction gains, drip ammoniacal liquor after completion of the reaction, regulate pH value to 3.5～4, generate throw out, reaction vessel is shifted out after cryogenic thermostat reactive bath technique, in reaction vessel, add purified water dissolution precipitation thing, add again ammoniacal liquor to regulate pH value to 8～9, generate again throw out, add trichloromethane dissolution precipitation thing, filter to get filtrate, by filtrate stratification, remove supernatant liquid, lower floor's organic phase is spin-dried for, drain in a vacuum, obtain dark-brown vincristine(VCR) crude product.
2. the synthetic method of vincristine(VCR) according to claim 1, is characterized in that: vincristine(VCR) crude product is carried out to purifying, obtain vincristine(VCR) purifying product, the purifying of vincristine(VCR) crude product comprises the steps:
1. trichloromethane: anhydrous methanol=99.5:0.5 by volume, trichloromethane is mixed with anhydrous methanol and is mixed with eluent 1, first in chromatography column, add part eluent 1 rinse chromatography column, take again 200～300 object column layer chromatography silicone rubbers, column layer chromatography silicone rubber is joined in remaining eluent 1, after stirring, pack in chromatography column cut-out tap after chromatography column is walked completely into;
2. trichloromethane: anhydrous methanol=99:1 by volume, trichloromethane is mixed to preparation eluent 2 with anhydrous methanol, press mass volume ratio vincristine(VCR) crude product: trichloromethane=0.56g/mL～0.7g/mL, vincristine(VCR) crude product is added in trichloromethane, after dissolving completely, add in chromatography column, eluent 2 is carried out to wash-out with the flow velocity of 45～55mL/min to chromatography column, until sample colour band is down to chromatography column bottom, till color appears in receiving bottle;
3. change sample colour band, trichloromethane by volume: anhydrous methanol=98.5:1.5, mixes trichloromethane and is mixed with eluent 3 with anhydrous methanol, eluent 3 is carried out to wash-out with the flow velocity of 45～55mL/min to chromatography column, until sample colour band is down to pillar bottom, change receiving bottle, eluent 4 taking volume as chromatography column volume repeats chromatography column to carry out wash-out with the flow velocity of 45～55mL/min again, taking eluent 3 as benchmark, when each repetition elution chromatography post, in eluent 4, the content of anhydrous methanol increases progressively 0.5% when the more last wash-out of volumn concentration of anhydrous methanol, when the more last wash-out of volumn concentration of trichloromethane, the content of trichloromethane successively decreases 0.5%, start to receive the liquid of chromatographic column effluent simultaneously, the liquid of chromatographic column effluent is receiving liquid, and detect the purity of vincristine(VCR) in receiving liquid, in the time of purity >=60% of vincristine(VCR) in receiving liquid, start to collect receiving liquid, in the time of the purity <60% of vincristine(VCR) in receiving liquid, stop collecting receiving liquid,
4. the receiving liquid of collection is carried out to concentrated by rotary evaporation, revolving and steaming temperature is 26～30 DEG C, pressure is-0.1MPa～-0.08MPa, revolve and steam to till not having reflux solvent to drip in return line 3 seconds, the enriched material now revolving after steaming is sticky silk fabric shape, stop revolving steaming, then enriched material vacuum is drained, obtain vincristine(VCR) purifying product.
3. the synthetic method of vincristine(VCR) according to claim 2, the method that it is characterized in that detecting during step is 3. the purity of vincristine(VCR) in receiving liquid is as follows:
Sherwood oil by volume: trichloromethane: acetone: diethylamine=6:3:0.5:0.6, by sherwood oil, trichloromethane, acetone and diethylamine mix as developping agent, the vincristine(VCR) of purity >=70% is dissolved in to the vincristine(VCR) chloroform soln that obtains after trichloromethane in contrast, receiving liquid and vincristine(VCR) chloroform soln are analyzed with thin layer chromatography, colour band distribution situation after separating in thin layer chromatography board with vincristine(VCR) chloroform soln by ultraviolet analysis instrument for three purposed observation receiving liquid, colour band after both separate in thin layer chromatography board distributes when identical, this receiving liquid is detected to the purity of vincristine(VCR) in this receiving liquid by high performance liquid chromatography, in the time of purity >=60% of vincristine(VCR) in this receiving liquid, start to collect receiving liquid, when colour band after observing both with ultraviolet analysis instrument for three purposed and separating in thin layer chromatography board is distributed with difference, now vincristine(VCR) sample spot desalination, impure point is denseer, again this receiving liquid is detected to the purity of vincristine(VCR) in this receiving liquid by high performance liquid chromatography, in the time of the purity <60% of vincristine(VCR) in this receiving liquid, stop collecting receiving liquid.
4. the synthetic method of vincristine(VCR) according to claim 2, is characterized in that: vincristine(VCR) purifying product are refined, obtained vincristine(VCR), refining the comprising the steps: of vincristine(VCR) purifying product
Press mass volume ratio vincristine(VCR) purifying product: anhydrous methanol=1:2g/mL, vincristine(VCR) purifying product are added in dehydrated alcohol, under 38～42 DEG C of water bath condition, dissolve, after dissolving completely, use ultrasonic echography, after having Precipitation, at-20～-30 DEG C, refrigerate, until Precipitation is complete, use solvent filter suction filtration, filter cake is washed with anhydrous methanol, again the filter cake after washing is dissolved with enough methylene dichloride, after dissolving, be spin-dried for, vacuum is drained, to drain gains and carry out recrystallization with anhydrous methanol at-20～-30 DEG C, at least recrystallization 5 times, obtain white vincristine(VCR).
5. the synthetic method of vincristine(VCR) according to claim 4, it is characterized in that: will drain gains and carry out recrystallization 5 times with anhydrous methanol under-20～-30 DEG C of conditions, the volume of the anhydrous methanol adding when each recrystallization is followed successively by drains 2.2,2.4,2.8,2.6 and 3 times of gains quality.
6. the method based on the synthetic vincristine sulphate of method described in claim 1, is characterized in that comprising the steps:
1) preparation of vincaleucoblastine
Vincaleucoblastine vitriol is added to the water, being mixed with concentration is the vincaleucoblastine sulfate liquor of 0.2～0.26g/mL, then add ammoniacal liquor to regulate pH value to 7.5～8 of vincaleucoblastine sulfate liquor, add again enough methylene dichloride to extract, after layering, remove supernatant liquid, lower floor's organic phase is spin-dried for, in vacuum, drain, obtain vincaleucoblastine;
2) vincristine(VCR) is synthetic
Vincaleucoblastine is dissolved in tetrahydrofuran (THF), being mixed with concentration is the vincaleucoblastine tetrahydrofuran solution of 0.02～0.025g/mL, then the reaction vessel that fills vincaleucoblastine tetrahydrofuran solution is placed in to cryogenic thermostat reactive bath technique, acetic acid is added in vincaleucoblastine tetrahydrofuran solution, wherein the mass volume ratio of vincaleucoblastine and acetic acid is vincaleucoblastine: acetic acid=0.25～0.3g/mL, , in the time that the temperature of cryogenic thermostat reactive bath technique is down to-63～-67 DEG C, insulation, under constant temperature, drip the sodium dichromate solution of concentration as 0.15～0.2g/mL taking the speed of 10～15mL/min, wherein the mass ratio of vincaleucoblastine and sodium dichromate 99 is vincaleucoblastine: sodium dichromate 99=1:1.60, in reaction gains, drip ammoniacal liquor after completion of the reaction, regulate pH value to 3.5～4, generate throw out, reaction vessel is shifted out after cryogenic thermostat reactive bath technique, in reaction vessel, add purified water dissolution precipitation thing, add again ammoniacal liquor to regulate pH value to 8～9, generate again throw out, add trichloromethane dissolution precipitation thing, filter to get filtrate, by filtrate stratification, remove supernatant liquid, lower floor's organic phase is spin-dried for, drain in a vacuum, obtain dark-brown vincristine(VCR) crude product,
3) vincristine sulphate is synthetic
By vincristine(VCR) crude product carry out purifying and refining after the vincristine(VCR) of gained be dissolved in and in ethanol, obtain vincristine(VCR) ethanolic soln, wherein the mass volume ratio of vincristine(VCR) and ethanol is vincristine(VCR): ethanol=1:3g/mL, under agitation condition, drip the ethanol solution of sulfuric acid of concentration of volume percent as 5% in taking the speed of 20～30mL/min to vincristine(VCR) ethanolic soln, produce white precipitate, in the time that the pH of solution value is 3.8～4.1, adding quality is the ethanol that boils of 30 times of vincristine(VCR) quality, at-20～-30 DEG C, refrigeration is complete to precipitation again, suction filtration, by filter cake ice washing with alcohol, after vacuum is drained, carry out normal temperature drying under reduced pressure and must be dried thing, to be dried thing further refining, obtain white vincristine sulphate.
7. the method based on the synthetic vincristine sulphate of method described in claim 1 according to claim 6, is characterized in that step 3) in dry the refining of thing comprise the steps:
Dry thing is dissolved by enough purified water, be then placed in freeze drier cold-trap, at-53～-57 DEG C, after precooling, drying under reduced pressure, obtains white vincristine sulphate.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104370911A (en) * | 2014-12-13 | 2015-02-25 | 海南希源化工科技有限公司 | Catharanthine tartrate preparation method |
| CN107880064A (en) * | 2017-10-09 | 2018-04-06 | 广州普星药业有限公司 | A kind of method of semi-synthetic vincristine sulphate |
| CN108558913A (en) * | 2018-03-23 | 2018-09-21 | 海南长春花药业有限公司 | A kind of preparation method of vincristine sulphate |
| CN115540503A (en) * | 2022-10-28 | 2022-12-30 | 广州白云山汉方现代药业有限公司 | Programmed drying method under vincristine sulfate ternary solvent system |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370911A (en) * | 2014-12-13 | 2015-02-25 | 海南希源化工科技有限公司 | Catharanthine tartrate preparation method |
| CN107880064A (en) * | 2017-10-09 | 2018-04-06 | 广州普星药业有限公司 | A kind of method of semi-synthetic vincristine sulphate |
| CN108558913A (en) * | 2018-03-23 | 2018-09-21 | 海南长春花药业有限公司 | A kind of preparation method of vincristine sulphate |
| CN108558913B (en) * | 2018-03-23 | 2020-06-19 | 海南长春花药业有限公司 | Preparation method of vincristine sulfate |
| CN115540503A (en) * | 2022-10-28 | 2022-12-30 | 广州白云山汉方现代药业有限公司 | Programmed drying method under vincristine sulfate ternary solvent system |
| CN115540503B (en) * | 2022-10-28 | 2024-04-23 | 广州白云山汉方现代药业有限公司 | Programme drying method of vincristine sulfate in ternary solvent system |
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Application publication date: 20140806 |